Hydroxypykimidine derivatives



Patented June 15, 1948 UNITED STATES PATENT OFFICE 2,443,303 I vnrnaoxvrvanvnpms DERIVATIVES Great Britain No Drawing. ApplicationAugust 28, 1945, Serial 7 Claims. 1

This invention relates to the manufacture of ney pyrimidine compoundswhich are useful as intermediates in the manufacture of chemotherapeuticagents and especially of the parasiticidal agents of copendingapplication Serial No. 613,218 of even date herewith.

The said new compounds are pyrimidine derivatives of the formulawhereinX is hydrogen or a hydrocarbon radical, Y is hydrogen or a neutralsubstituent, such, for example, as a hydrocarban radical, an al koxy oraryloxy or alkylmercapto group, or a cyano group, and also X and Y maybe joined together to form an alkylene chain, and of the groups Z and Z,one is a hydroxy group, and the other is a substituted amino group ofthe form NR"A-NRR wherein R" is hydrogen or an alkyl or simplysubstituted alkyl group, for example, an alkoxyalkyl ordialkylaminoalkyl group, A is a linking group which is aliphatic oralicyclic or aliphatic-carbocyclic and may be substituted, for example,by hydrocarbon radicals, or alkoxy or dialkylaminoalkyl groups and,where A or part of A is an aliphatic chain, it may be interrupted byoxygen, nitrogen or sulphur atoms and NRR' is an amino or substitutedamino group such as acylamino or alkylamino or dialkylamino orpiperidino or other strongly basic nitrogen-containing heterocyclicgroup.

We make the said new compounds by a prcess comprising the interaction ofa 2- or 4-hydroxypyrimidine bearing the groups Y and X in the 5- and6-positions respectively and in the 4- or Z-position an alkylmercapto orsubstituted .alkylmercapto group, with a diamine NHR. '-A

NEE wherein A, R" and NRR have the same meanings as before.

As examples of diamines suitable for use as starting materials there maybe mentioned ethylene diamine, 2-dimethylaminoethylamine,Z-diethylaminoethylamine, 3 dimethylaminopropylamine,3diethylaminopropylamine, 3-di-nbutylaminopropylamine,4-dimethylaminobutylamine, 4-diethylaminobuty1arnine,4-di-n-butylaminobutylamine (B. P. 135-136 C./18 mm.

.made by sodium and ethanol reduction of 4-din-butylaminobutyronitrileitself made by interaction of 4-bromobutyronitrile with dibutylamine)i-diethylamino-l-methylbutylamine, 5-

. dimethylamino-n-amylamine, 5 diethylaminon-amylamine, 3 diethylamino1:2 dimethyl- In Great Britain September 25,

2 propylamine, 6-dimethylaminohexylamine (B. P. 111 C./18mm., made bysodium and ethanol reduction of fi-dimethylaminocapronitrile, itselfobtained by interaction of 1:5-dibromopentane with one molecularproportion of sodium cyanide and subsequent interaction of theS-bromocapronitrile so obtained with dimethylamine), 3-diethylamino,2-hydroxypropylamine, 2-methylaminoethylamine, 3 butylaminopropylamine,2-acetylaminoethylamine, 3 (,6 diethylaminoethoxy) -propylamine, 3(B-diethylaminoethylmercapto) -propylamine, 2-pyrrolidinoethy1amine, 1 3-bis-diethylamino-2-aminopropane, N-ethyl- N s diethylaminoethylethylene diamine, 2- piperidinoethylamine, 2-piperidino 1methylethylamine, 2 piperidino n propylamine, 3- piperidino-npropylamine, p diethylaminoethoxy-aniline, pdiethylaminoethylmercaptoaniline, 3 diethylamino 2:2 dimethylpropylamineand N-methyl-N- 3-diethy1aminoethyl+ propylenediamine.

As examples of suitable mercapto compounds there may be mentioned2-methylmercapto-4- hydroxypyrimidine, Z-methylmercapto 4hyclroxy-6-methylpyrimidine, 2 methylmercapto 4-hydroxy-6-ethylpyrimidine, 2 methylmercapto-i-hydroxy-6 phenylpyrimidine, 2ethylmercapto-4-hydroxy-(i-methylpyrimidine,2-benzylmercapto-4-hydroxyG-methylpyrimidine, 2-hydroxyl-methylmercapto6 methylpyrimidine, 2-methylmercapto-4-hydroxy 5:6-dimethylpyrimidine,2-methy1mercapto-4-hydroxy-5-ethyl- 6-methylpyrimidine, 2 ethylmercapto4 hydroxy-5-phenylpyrimidine, 2 ethylmercapto-4-hydroxy-5-methylpyrimidine, 2-ethylmercapto-4:-hydroxy-5-phenoxypyrimidine, 2-ethy1mercapto-4-hydroxy-5-benzyl-6methylpyrimidine, 2- methylmercapto-4 hydroxy 5:6:728tetrahydroquinazoline and Z-methy-lmercapto 4 hydr0xy-5:6-trimethylenepyrimidine.

The condensation of the alkylmercaptopyrimidine with the diamine isconveniently brought about by heating the reagants together, optionallyin the presence of an inert solvent or diluent, such as s-ethoxyethanol,whereupon the alkyls mercaptan iseliminated and the new substitutedaminopyrimidine derivative is formed.

Where the diamine used is of the form NH2A-NH2 it is preferable to usean excess thereof to suppress or minimize the unwanted side-reactionwherein one molecular proportion of the diamine combines with twomolecular proportions of the pyrimidine derivative.

Where it is desired to introduce a. substituent of the .form NR.ANH2itis necessary to use as the starting material an acylated derivative inwhich the primary amino group of the diamine has been protected byacylation, to condense this with the 2-alkylmercapto-4-hydroxypyrimidineand then subsequently to remove the acyl group, as by hydrolysis with adilute mineral acid.

The new pyrimidine derivatives obtained in accordance with thisinvention are colourless or pale yellow viscous oils or low-meltingsolids which are soluble in water. They readily form salts with organicand inorganic acids; the picrates, 3 -clinitrobenzoates anddihydrochlorides, for instance are useful for ready characterization ofthe compounds. In those compounds wherein the basic substituent containsa :primary amino group this can readily be alkylated or converted to aheterocyclic ring such as a piperidino radical by the methodscustomarily used for effecting such conversions, for example heatingwith an alkyl iodido or with di-methyl sulphate or pentamethylenedibromide.

The 2-alkylmercapto-4-hydroxy pyrimidines used as starting materials mayconveniently be made by interaction of appropriate alkyl isothioureaswith formylacetie esters appropriately substituted, Where necessary, onthe aand/or B-carbon atoms, or by direct S-alkyla'tion of the 2 mercapto4 hydroxypy-rimidines themselves obtained from thiourea andformyl-acetic esters appropriately substituted, where necessary, on theaand/or fl-carbon atoms. The alternative starting materials, the'2-hydroxy-4-alkylmercaptopyrimidines may be made from the 2-alkylmercapto 4 hydroxy compounds by the following method. The 4-hydroxygroup is converted to chloro by treatment with POCla and thence, bymeans of sodium or potassium hydrogen sulphide, to SH; acid hydrolysisof the 2-a'lk-ylmercapto group then gives the Z-hydroxy- 4-mercaptocompound which is S-alkylated (cf. Wheeler and McFarland, AmericanChemical Journal 1909, 42, 431).

The following examples, in which the parts are by weight, illustrate butdo not limit the invention.

Example 1 v 31.2 parts of 2-methylmercapto 4 hydroxy-G- methylpyrimidineand 23.2 parts of .B-diethylaminoethylamine are heated together at 160-180 C. for 3 hours. Rapid evolution of methylmercaptan occurs and acolourless viscous oil is formed. This is substantially pure 2-8-di'ethy1 aminoethylamino-4-hydroxy 6 methylpyrimi- Example 22-'y-diethylaminopropylamino 4 hydroxy-6- methylpyrimidin-e, dipicrateM. P. 2 11--2 12 C.

Example 3 2-6-diethylaminobutylamino 4 .hydroxy 6- methylpyrimidine,dipicrate M. P. 209 C.

Example 4 2-' -dimethylaminopropylamino- 4 -hydroxy-6- methylpyrimidine,dipicrate M. P. 201-202 C.

Example 5 '2- y-dibutylaminopropylamino 4 hydroxy-G- methylpyrirnidine,dipicrate M. P. 224-225 C.

Example 6 2-' -piperidinopropylamino 4 hydroxy 6- methylpyrimidine,dihydrate M. P; 81-82 C., dipicrate M. P. 218 C.

' Example 7 2,-6-diethylamino amethy1butylamino=4-hydroxy-fi-methylpyrimidine, dipicrate M. P. 1'l2 C.

Example 8 2-v-butylaminopropylamino 4 hydroxy 6- methylpyrimidine,dipicrate M. P. 200, bis-3:3- dinitrobenzoate M. P. 193-194 C.

Example 9 2-'y -(e- .diethylaminoethoxy) propylamino-4-hydroxy-6-methylpyrimidine, .dipicrate M. P. 161-163 C. I

Example 10 Example 11 2-(N methyl-N'-e diethylaminoethyl-amino)4-hydroxy-G-methylpyrimidine, 'dipicrate. M. P. 167-169 C.

Example 12 Example 13 By working in the same way but using 7--dibutylaminopropylamine instead of the 'Y-diethylaminopropylamine thereis obtained 2-7-dibutylaminopropylamino-4-hydroxy 5 ethyl-6-methylpyrimidine. It forms a mono picrate of M. P. 18'2-1'83 C. anda'd'ipicrate of M. P. 166- 1-67" C.

Example 14 15.6 parts of 2-hydroxy-4-methylmercapto6 methylpyrimidineand 11.6 parts of fi-die'thylaminoethylamine are heated together at1'600. for 2 hours. A homogeneous liquid is formed, methyl mercaptan isevolved and after about half an hour the mass'sets solid. The2-hydroxy-4-fi-diethylaminoethylamino-G-methylpyrimidine thus.

formed may be purified by crystallisation from a mixture of ethanol andethyl acetate. When pure it melts at 230-232 C. It forms a diplcratewhich crystallises from B-ethoxyethanol in yellow laminae of M. P.223-224 C. and a dihydrochloride which crystallises from ethanol incolourless needles of M. P. 258-260 C. (decomp.)

By working in a similar way but using other appropriate diamines insteadof the c-diethylaminoethylamine there are obtained the following furthercompounds. A

Example 15 Example 16' 'Z-hydroXy 4 6 -diethylamino-a-methyl-butylamino-fi-methylpyrimidine The crude material is boiled with benzene andthe extract is discarded. The residue, crystallised from ethyl acetategives a hygroscopic hydrate of M. P. 134"- 140" C. The picrate,crystallised from a mixture of ethanoland fi-etlioxyethanol has M; P.181- 182 C.

Example 17 5.7 parts of Z-methyImercaptQ- l-hydroxy-5 6-dimethylpyrimidine and 7.7 parts of v-dibutylaminopropylamine are heatedtogether under reflux at 160 170 C. for 3 hours. The excess of thediamine is then distilled off under diminished pressure and the residueis distilled from a bath at 2(a0"--2tl0C./10- mm. There is thus obtained2- 'y -dibutylaminopropylamino- 4 -hydroxy- 5:6--dimethylpyrimidine inthe form of a viscous oil. The dipicrate crystallises from alcoholinyellow needles of M. P. 199-202 C.

Example 18 By working in a similar manner but using 4.3 parts offl-diethylaminoethylamine instead of the -dibutylaminopropylamine, thereis obtained 2-;8- diethylaminoethylamino- 4-hydroxy-5:6-dimethylpyrimidine in the form of a pale yellow oil whichcrystallises when triturated with petroleum ether (B. P. 60-80 C.). Thenew compound is recrystallised from petroleum ether and then has M. P.69-71 C.

Example 19 17 parts of Z-methylmercaptol-hydroxypyrimidine and 22.3parts of y-dibutylaminopropylamine are heated together at 160-180 for 2hours. There is a brisk evolution of methyl mercaptan and a colourlessviscous oil is formed. This is substantially pure 2--dibutylaminopropylamino-4-hydroxypyrimidine. It forms a dipicrate whichafter crystallisation from fi-ethoxy= ethanol has M. P. 198-199 C.

Example 20 Example 21 31.2 parts of 2-methylmercapto-4-hydroxy-6-methylpyrimidine are added to a solution of 40 parts of ethylene diaminein 100 parts of fl-ethoxyethanol and the mixture is heated to 100- 110C. for 16 hours. The clear solution so formed is evaporated in vacuo andthe residue is dissolved in 230 parts of hot water. A small amount ofimpurity remains undissolved and is filtered oil. The filtrate isevaporated to dryness in vacuo and the residue is thoroughly dried andthen crystallised from ethanol. There is thus obtained 1-5.6 parts of2-methylmerc'apto-4-hydroxy-6- methylpyrimidine and 10.2 parts ofmonoacetylethylene diamine are heated together at --160 C. for 3 hours.The solid so formed is then crystallised from a mixture of ethanol andethyl acetate. There isthus obtained Z-B-acetylaminoe'thylamino-4-hydroxy-S-methylpyrimidine of M. P. 144146 C. (decomp.).i

The acetyl group can be removed by heating with dilute hydrochloricacid, neutralising with the stoichiometric proportion of caustic soda,evaporating the solution to dryness, extracting the residuevwithcthanoland concentrating the ethanol solution to crystallisation. Thereisthus obtained 2-,6-aminoethylamino-4-hydroXy-6-metl'i+ ylpyrimidine ofM. P. 176-17'7 C.

Whereas the above description and examples illustrate many widelyvarised embodiments of the invention it will be apparent to one skilledin the art that many other embodiments and variations may be devisedwithout departing from the spirit and scope thereof and accordingly itis to be understood that the invention is not in any way limited exceptas defined in the following claims:

We claim: 1. A compound of the general formula i=2 Z-fil EIJY N-O-OHwherein X designates a member of the group consisting of hydrogen andhydrocarbon radicals, Y is a member of the group consisting of hydrogenand hydrocarbon, while Z designates a diamine radical; said diamineradical having the form --NH--A--NRR., wherein NPR is a strongly basicradical selected from the group consisting of primary, secondary andtertiary amine radicals and heterocyclic nitrogenous base radicals,while A is an organic radical linking the two N-atom-s Of the diamineand interposing therebetween at least two aliphatic carbon atoms.

2. A compound of the general formula wherein Y is a member of the groupconsisting of hydrogen and hydrocarbon, Z designates a diamine radicalhaving the form NHANRR' wherein NRR' is a strongly basic radicalselected from the group consisting of primary, secondary and tertiaryamine radicals and heterocyclic nitrogenous base radicals, while A is anorganic radical linking the two N-atoms of the diamine and interposingtherebetween at least two aliphatic carbon atoms.

3. A compound of the general formula wherein Z designates a diamineradical having the form --NH-A-NRR, wherein NRR is a strongly basicradical selected from the group consisting of primary, secondary andtertiary amine radicals and heterocyclic nitrogenous base radicals,while A is an organic radical linking the two N-atoms of the diamine andinterposing '7 therelactween at least two aliphatic carbon atoma 4. Acompound of thegeneral. formula- R rg=o-om m-alkwNwo on 1 ll a N -o11wherein alk designates an alkylene radical which interposes at least 2and, not more than 6, carbon atoms between the two N-atoms, R" standsfor a. member of the group consisting of hydrogen and alkyl, while is astrongly basic radical selected from the group consisting of primary,secondary and tertiary amine radicals and heterocyclic nitrogenous baseradicals.

5. A compound of the general formula B. N=0CHa.

Nalk-NHO 1 H H: II a NC-0-H REFERENCES CITED The following referencesare of record in" the file of this: patent:

American Chemical Journal, vol. 33 ('1905'), pp; 439 and 449.

Jour. American Chem. Soc, vol. 67 (1945) pp;

1159-61, s Survey of Antimalarial Drugs, vol. 2,'part 2:, page 1403',(1946). Y V

